Chemical Name: (S)-1-(1H-benzo[d]imidazol-5-yl)-5-(4- propoxyphenyl)imidazolidin-2-one
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Probiodrug AG, Vivoryon Therapeutics N.V.
PQ912 is an inhibitor of glutaminyl cyclase (QC), aka glutaminyl-peptide cyclotransferase (QPCT). This metalloenzyme is upregulated in the brains of Alzheimer’s disease patients. QC generates pyroglutamate Aβ, a modified, pathogenic form of the peptide, by catalyzing the cyclization of an exposed glutamate at the N-terminus of Aβ. The enzyme has been reported to be highly expressed in affected cortical regions in AD; the resulting pGlu-Aβ has been found to be toxic, highly aggregation-prone, and a major component of amyloid plaques in humans (Apr 2008 conference news; Morawski et al., 2014; Frost et al., 2013).
PQ912 represents a small-molecule approach to reducing pGlu-Aβ generation; an immunotherapy targeting this pathogenic species directly exists, as well (see donanemab).
In preclinical work, QC inhibitors have been reported to reduce amyloid pathology and improve performance in learning and memory tests in various mouse models (Apr 2008 conference news; Schilling et al., 2008). In mice doubly transgenic for human APP and glutaminyl cyclase, chronic oral dosing with PQ912 was reported to reduce brain pyroglutamate Aβ and improve recall in the Morris water maze test of spatial memory (Hoffmann et al., 2017). The combination of PQ912 and an pGlu-Ab-specific antibody additively reduced Aβ in mouse brain (Hoffmann et al., 2021).
The first clinical trial of PQ912 was not listed in clinicaltrials.gov; however, its results were presented at the 2013 AD/PD conference in Florence, Italy. In a single-center Phase 1 study in Switzerland, 108 healthy volunteers up to age 50 received once- or twice-daily doses ranging from 20 to 500 mg of PQ912, either in liquid or pill form; 28 received placebo. The drug’s half-life in CSF was reported to be longer than in plasma, with CSF concentrations a third of those in blood. The concentration that was reached in CSF blocked QC activity. The compound's pharmacokinetic and pharmacodynamic properties reportedly were dose-proportional; for details see Mar 2013 conference news. In this trial, PQ912 appeared safe and well-tolerated up to the highest dose tested. As presented at the subsequent 2013 AAIC conference in Boston, PQ912 was safe in an extension trial evaluating 200 to 300 mg/day in 16 elderly volunteers, as well. The complete Phase 1 data is published (Lues et al., 2015).
Many candidate drugs either activate or deactivate enzymes of the P450 detoxification complex in the liver and intestine. To assess this possibility, Probiodrug, via the CRO Covance, started a single-center trial in the U.K. in June 2014 that measured the inhibition of CYP3A and CYP2C19 in 18 healthy volunteers. This trial uses the benzodiazepine midazolam and the antacid omeprazole, which are metabolized by CYP3A and CYP2C19, respectively, as probes to measure whether PQ912 affects P450. This study was completed in August 2014 but no results have been published.
From March 2015 to April 2017, the Phase 2 SAPHIR trial compared a 12-week course of twice-daily 800 mg PQ912 tablets to placebo. It enrolled 120 people with MCI or mild dementia due to AD as ascertained by CSF Aβ levels at screening. This trial took place in seven European countries. It met its primary outcome of safety, with no difference in the frequency of adverse events between the treatment and placebo arms. The treatment group had more skin reactions and gastrointestinal problems than placebo, and more discontinuations. PQ912 inhibited QC activity in CSF by 92 percent. It appeared to slightly decrease pyroglutamate Aβ oligomers in CSF, though CSF Aβ oligomers' concentrations are near the assay’s detection limit. The treatment group showed a benefit on working memory and a trend on attention, but no difference on five other neuropsychological tests. On EEG readings, the treatment group showed a reversal of AD-induced changes in theta and alpha rhythms. In CSF, the synaptic marker neurogranin and the inflammatory marker YKL40 trended downward from a known rise in AD. CSF AD biomarkers were unchanged (Jun 2017 news; Scheltens et al., 2018; Briels et al., 2020).
In 2019 Probiodrug became Vivoryon Therapeutics.
In July 2020, the Phase 2a/b VIVIAD study began to enroll 259 early stage Alzheimer’s patients in Denmark, Germany, and The Netherlands. A 24-week dose finding phase is testing 300 or 600 mg twice daily versus placebo, followed by up to 96 weeks treatment at the highest safe dose. The primary endpoints are safety, and efficacy on working memory and attention. Secondary endpoints include long-term safety and effects on brain activity, cognition, and daily functioning. The trial is also collecting exploratory data on the Winterlight speech-based cognitive assessment, EEG, and blood biomarkers. For more details, see the published protocol (Vijverberg et al., 2021).
In November 2021, Vivoryon began another Phase 2a/b trial, this time in the U.S., and in collaboration with the U.S. National Institutes on Aging and the Alzheimer’s Disease Cooperative Study. The VIVA-MIND study is enrolling 414 participants with biomarker-confirmed early AD and MMSE scores between 20 and 30. The initial part of this safety and efficacy trial will titrate 180 patients in three groups to target doses of 150 mg, 300 mg, or 600 mg twice a day for at least 24 weeks, or placebo. Primary outcomes are safety, plasma levels, ADNI cognitive battery composite scores, and quantitative EEG. Based on the results, investigators will calculate target occupancy in CNS, and continue dosing these and additional participants at a level aiming for 50 percent occupancy for 72 weeks, or placebo. The primary efficacy outcome is change in CDR-Sum of Boxes from baseline to 72 weeks; secondary outcomes include the cognitive function composite CFC2 score. Study completion is expected in November 2023.
In December 2021, the U.S. FDA granted Fast Track status to varoglutamstat.
In June 2022, the company announced completion of the dose-finding phase of VIVIAD. Based on data from 181 patients, an independent safety monitoring board selected the highest dose tested, 600 mg twice daily, for the rest of the study (press release). Trial results are expected in the second half of 2023.
Clinical Trial Timeline
- Phase 2
- Study completed / Planned end date
- Planned end date unavailable
- Study aborted
Last Updated: 08 Feb 2023
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